Cellularity of mucus is a prognostic variable in low-grade appendiceal mucinous neoplasms.

For peritoneal metastases from a primary appendiceal mucinous neoplasm to exist, the thin wall of the appendix must perforate to allow mucus or mucus plus tumor cells to gain access to the peritoneal spaces. The proportion of specimens containing tumor cells within mucus as compared to mucus only outside the appendix may have prognostic significance. The histopathology of tumor masses was determined from the specimens resected at the cytoreductive surgery (CRS). The presence versus absence of tumor cells in mucus and the proportion of specimens with tumor cells was determined and correlated with the overall survival of these patients. In 418 patients with a complete cytoreduction for a low-grade appendiceal mucinous neoplasm (LAMN), the cellularity of all resected specimens was determined. The hazard ratio of overall survival of patients whose specimens had no cells as compared to specimens with cells in mucus by histology was 4.41 (1.61, 12.1) (p = 0.0039). If overall survival of patients with all specimens without tumor cells was compared to patients with specimens with 1-99 % tumor and compared to patients with 100 % of specimens with tumor cells, the hazard ratios were 4.3 (1.34, 13.8) (p = 0.0143) and 9.62 (2.93, 31.6) (p = 0.0002), respectively. The cellularity of mucus within the specimens removed by a complete CRS has strong prognostic implications in LAMN patients. LAMN with acellular specimens (LAMNa) as compared to LAMN with tumor cells in specimens (LAMNb) should be staged as different histologic subtypes of mucinous appendiceal neoplasms.

Coronary artery bypass grafting for triple vessel disease in cardiac amyloidosis.

Cardiac amyloidosis is a rare condition with an estimated incidence of 18-55 per 100 000 person-years. It is associated with either immunoglobulin light chain (AL) or transthyretin amyloid (ATTR), both of which result in a restrictive cardiomyopathy complicated initially by diastolic dysfunction and subsequently followed by biventricular systolic heart failure. Untreated cardiac amyloidosis carries an extremely poor prognosis with an estimated median survival time of less than 1 year in AL and 4 years in ATTR amyloidosis. This is the sixth described report of coronary artery bypass grafting in patients with underlying cardiac amyloidosis.

Similar Survival Among All Subtypes of Mucinous Appendiceal Adenocarcinoma Except the Intermediate Subtype, Which Shows an Improved Survival.

BACKGROUND: Limited success in the management of mucinous appendiceal adenocarcinoma (MACA) has been reported. METHODS: Cytoreductive surgery with perioperative intraperitoneal chemotherapy was used to treat a cohort of patients with peritoneal dissemination of MACA. The clinical and histopathologic variables were assessed for their impact on overall survival. RESULTS: The study analyzed 196 patients during a median follow-up period of 8 years. The patients had a median age was 46 years, a median survival of 12 years, and a mean survival of 12.4 years. Preoperative systemic chemotherapy and a high prior surgical score had a negative impact on prognosis. Survival was better for 37 patients (18.9%) with mucinous appendiceal adenocarcinoma-Intermediate (MACA-Int) histology than for 159 patients (81.1%) with MACA grade 1, 2, or 3, or signet ring cells (S) (p = 0.0004). Although MACA-1 and MACA-2 versus MACA-3 and MACA-S had a difference in survival of 63.9 versus 43.2 years at 5 years, with long-term follow-up evaluation, the differences in survival became insignificant (p = 0.5841). CONCLUSION: The histologic subtype of MACA-Int had a 10-year survival of 81.1%, which was markedly superior to that of MACA-1, -2, -3, or -S (32.7%). With long-term follow-up evaluation, MACA-1, -2, -3, and -S did not differ significantly in survival.

Use of direct-acting antivirals for hepatitis C viral infection and association with intrahepatic cholangiocarcinoma: Is there a linkage?

Hepatitis C viral infection is recognized worldwide as a leading cause of cirrhosis and hepatocellular carcinoma. The goal of hepatitis C viral antiviral therapy is the permanent eradication of hepatitis C viral RNA, commonly referred to as a sustained virologic response - defined as "undetectable" RNA at 12 weeks following the completion of therapy. Hepatitis C viral treatment has dramatically advanced with the FDA approval of several new agents known as direct-acting antivirals. These drugs target specific nonstructural proteins of the virus, which disrupt viral replication, and therefore halt infection. However, recently, there has been a concern for increased risk of recurrence of treated hepatocellular carcinoma or denovo occurrence of hepatocellular carcinoma after treatment with direct-acting antivirals. We are now reporting three cases of intrahepatic cholangiocarcinoma that developed after sustained virologic response following hepatitis C viral treatment with direct-acting antivirals.

High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, have been shown to mediate invasiveness and metastatic behavior in a number of cancers, including ovarian, prostate, bladder, breast, and pancreatic cancers. The expression and significance of SDF-1 in pancreatic ductal adenocarcinoma (PDA) have not been systematically studied. METHODS: We examined the expression of SDF-1 by immunohistochemistry using a mouse anti-human SDF-1/CXCL12 antibody (dilution 1:300) and a tissue microarray consisting of 72 stage II PDAs from pancreaticoduodenectomy specimens. The staining results were categorized as SDF-1-high (SDF-1-H; cytoplasmic staining of ≥10% of tumor cells) or SDF-1-low (SDF-1-L; no staining or staining of <10% of tumor cells). The results of SDF-1 expression were correlated with clinicopathologic parameters and survival. Statistical analyses were done using SPSS software. RESULT: Of the 72 stage II PDAs, 25 (35%) showed high levels of SDF-1 expression. The median overall and recurrence-free survival for patients with SDF-1-H PDAs were 26.1 and 11.1 months, respectively, compared with 44.3 and 22.3 months for patients with SDF-1-L tumors (log-rank test, P = 0.047 and P = 0.021). In multivariate analysis, high SDF-1 expression correlated with poor overall and disease-free survival (P = 0.02 and P = 0.02) independent of tumor size, differentiation, and lymph node status. CONCLUSION: High levels of SDF-1 expression were associated with poor overall and disease-free survival in patients with stage II PDA. SDF-1 may serve as a useful prognostic marker for stage II PDA. IMPACT: Our results suggest that SDF-1-CXCR4 or SDF-1-CXCR7 pathways may represent a potential target for therapeutic intervention as well as prediction of prognosis in PDA.

Diagnosis and management of retroperitoneal ancient schwannomas.

BACKGROUND: Ancient schwannomas are degenerate peripheral nerve sheath tumors that very rarely occur in the retroperitoneum. They generally reach large proportions before producing symptoms due to mass effect. We describe three cases of retroperitoneal ancient schwannomas and discuss the diagnosis and management of these tumors. CASE PRESENTATIONS: Three female patients with retroperitoneal ancient schwannomas were reviewed. One patient presented with several weeks of upper abdominal pain and lower chest discomfort, whereas back pain and leg pain with associated weakness were predominant symptoms in the remaining two. Abdominal imaging findings demonstrated heterogeneous masses in the retroperitoneum with demarcated margins, concerning for malignancy. The patients successfully had radical excision of their tumors. Histological examination showed encapsulated tumors that displayed alternating areas of dense cellularity and areas of myxoid matrix consistent with a diagnosis of ancient schwannoma. CONCLUSION: A diagnosis of ancient schwannoma should be entertained for any heterogeneous, well encapsulated mass in the retroperitoneum. In these cases less radical surgical resection should be considered as malignant transformation of these tumors is extremely rare and recurrence is uncommon following excision.

Diagnostic and prognostic biomarkers in pancreatic carcinoma.

Pancreatic ductal carcinoma, one of the leading causes of cancer mortality, is typically diagnosed at an advanced stage, which significantly contributes to its high mortality rates. Studies have demonstrated that resection of small pancreatic tumors and tumors at lower stages correlates with improved survival. Detection of pancreatic carcinoma at an early, surgically resectable stage is the key to decreasing mortality and improving survival. Identification of sensitive diagnostic biomarkers as screening tools is crucial in detecting preinvasive pancreatic neoplasms. Numerous new DNA-, RNA- and protein-based biomarkers have been extensively investigated. This review aims to provide an update on these molecular markers, including biomarkers from blood, tissue as well as pancreatic juice and cystic fluid. These biomarkers hold potential utility in early diagnosis and prognostification of pancreatic ductal carcinoma, though many of which need to be validated in large-scale prospective studies before they can be used in clinical settings.

Expression of MAP4K4 is associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma.

PURPOSE: Mitogen-activated protein 4 kinase 4 (MAP4K4) is a serine/threonine kinase and belongs to the mammalian STE20/MAP4K family. Recent studies have shown that MAP4K4 is overexpressed in many types of human cancer and cancer cell lines. MAP4K4 plays an important role in transformation, invasiveness, adhesion, and cell migration. However, the expression of MAP4K4 and its significance in pancreatic ductal adenocarcinoma (PDA) has not been studied. EXPERIMENTAL DESIGN: We examined the expression of MAP4K4 by immunohistochemistry using tissue microarrays consisting of 66 stage II PDA and their paired benign pancreatic tissue. The staining results were categorized as MAP4K4-H or MAP4K4-L. The results were correlated with clinicopathologic features and patient survival. RESULTS: MAP4K4 was overexpressed (MAP4K4-H) in 30 of 66 (46%) PDAs and was higher than the paired benign pancreatic tissue samples (19%; P=0.002). The median overall and recurrence-free survival for patients with MAP4K4-H PDAs were 19.5 and 9.3 months, respectively, compared with 65.2 and 28.8 months for patients with MAP4K4-L tumor (P=0.02 and 0.0005, log-rank test). MAP4K4 expression was associated with poor overall and recurrence-free survival in univariate analysis (P=0.02 and 0.001). In multivariate analysis, MAP4K4 expression significantly correlated with overall and recurrence-free survival (P=0.025 and 0.004) independent of age, tumor size, differentiation, and stage. MAP4K4 expression was also associated with higher frequency of recurrence/metastasis, larger tumor size, and increased number of positive lymph nodes (P<0.05). CONCLUSION: MAP4K4 was overexpressed in about half of PDAs. Overexpression of MAP4K4 was associated with worse prognosis and is a prognostic marker for stage II PDAs.

Nomenclature, molecular genetics and clinical significance of the precursor lesions in the serrated polyp pathway of colorectal carcinoma.

Serrated adenomas (SAs) are part of the distinct serrated polyp pathway of colorectal carcinogenesis characterized by microsatellite instability and deficiency in DNA mismatch repair. Sessile SA is a recently recognized lesion that typically presents as a large sessile polyp, but lacks the conventional dysplasia. It is more frequently found on the right side than on the left side of the colon, and is thought to represent an intermediate form in the hyperplastic polyp to sessile SA, traditional SA, and colon cancer sequence. Many terms have been used and are still in use in the literature to describe this lesion, such as "hyperplastic polyposis", "giant hyperplastic polyposis," "large hyperplastic polyps," "hyperplastic-adenomatous polyposis syndrome," "giant hyperplastic polyp," and "mixed epithelial polyp." The purpose of this paper is to review and clarify the confusing nomenclature, and to provide a framework for understanding the genetic alterations and clinical significance of these precursor lesions in the serrated polyp pathway of colorectal caner.

Carcinoid tumors arising in tailgut cysts may be associated with estrogen receptor status: case report and review of the literature.

Tailgut cysts are uncommon developmental cysts that form in the presacral space. Complications of tailgut cysts include benign reactive lesions associated with infection and inflammation, and malignant transformation. Six cases of carcinoid tumor arising in tailgut cysts have been reported in the medical literature to date. Here we report another case of carcinoid tumor arising in a tailgut cyst. Because six of seven cases occurred in females, we postulate that these tumors are hormone-associated. This hypothesis is supported by the present study. We found strong estrogen receptor immunoreactivity of the benign squamous and columnar cyst-lining cells as well as carcinoid tumor cells, in addition to neuroendocrine differentiation in the tumor cells and scattered cyst-lining cells. We speculate that estrogen receptor may be a potential therapeutic target in patients with this condition.

Activation of Akt-mTOR-p70S6K pathway in angiogenesis in hepatocellular carcinoma.

Angiogenesis is an essential process for progression of hepatocellular carcinoma (HCC). The Akt-mTOR-p70S6K signal pathway has been recognized for its roles in regulating neoangiogenesis. The role of activation of the pathway in HCC progression is poorly understood. This study aimed to evaluate the immunohistochemical expression of the phosphorylated forms of the three key constituent proteins (Akt, mTOR and p70S6K) of the Akt-mTOR-p70S6K signal pathway in HCC and non-HCC tissue. Formalin-fixed paraffin-embedded tissue sections of 51 HCC, 9 hepatocellular adenoma (HCA), 48 cirrhotic nodules (CN) and 17 normal liver tissues (NLT) were immunostained for p-Akt, p-mTOR and p-p70S6K. The number of p-Akt and p-p70S6K-positive sinusoidal endothelial cells (SEC) and the intensity of immunostaining were significantly increased in HCC compared with HA, CN and NLT (p<0.01). p-mTOR in SEC tended to have an increased expression in SEC in HCC versus non-HCC tissue (p>0.05). There was a significant correlation between a high p-Akt and p-p70S6K expression, and a venous and capsular invasion of HCC. Our results suggest that activation of the Akt-mTOR-p70S6K pathway plays a significant role in HCC progression by promoting neoangiogenesis. Molecular strategies aimed at inhibiting this signal pathway may be of therapeutic use for the treatment of HCC.

Significance of overexpression of alpha methylacyl-coenzyme A racemase in hepatocellular carcinoma.

BACKGROUND: alpha-Methylacyl-CoA racemase (AMACR), an immunomarker for prostatic adenocarcinoma, has been shown to be expressed in a variety of other neoplasms. This study aims to evaluate immunohistochemical expression of the AMACR in neoplastic and nonneoplastic liver lesions, and assess its value in the diagnosis of hepatocellular carcinoma (HCC). METHODS: Formalin-fixed paraffin-embedded tissue sections of 51 HCC (14 well, 22 moderately and 15 poorly differentiated), 9 hepatocellular adenoma (HCA), 48 cirrhotic nodules (CN) and 16 normal liver tissues (NLT) were immunostained for AMACR. RESULTS: Expression of AMACR is significantly enhanced in HCC tissue compared with non-HCC tissue. High expression of AMACR was found in 82% of HCC including 86% of well-differentiated HCC. In contrast, only 11% of HCA, 13% of CN and 6% of NLT showed high expression for AMACR. Clinicopathological evaluation showed a significant correlation between AMACR expression and venous invasion and capsular invasion by HCC. CONCLUSION: Our results suggest that AMACR staining may serve as a useful marker for the differential diagnosis of well-differentiated HCC from HCA. Increased AMACR expression and its association with tumor venous invasion suggest that AMACR may play a role in HCC development and progression.

The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors.

PURPOSE: The role of androgen receptor coactivators in testicular development and cancer formation is unclear. p44/Mep50 was identified as an androgen receptor coactivator that functions in a complex with protein arginine methyltransferase 5. We studied the expression of p44 and protein arginine methyltransferase 5 in developing fetal testis and adult testicular tumors, including seminomas and Leydig cell tumors. MATERIALS AND METHODS: A total of 30 human fetal testes from abortuses at a gestational age of 10 to 40 weeks, 33 human seminomas and 11 human Leydig cell tumors were retrieved from the archives of the departments of pathology. Immunohistochemistry was performed with affinity purified p44 and IgG purified protein arginine methyltransferase 5 polyclonal antibodies. RESULTS: Protein arginine methyltransferase 5 and p44 were expressed predominantly as nuclear proteins in fetal Leydig cells and human adult nonneoplastic testes, including germ cells and Leydig cells, while they were expressed in the cytoplasm of germ cells of the fetal testis. Expression was strongest in the fetal testis during the second trimester. Compared to adult nonneoplastic testes, human seminoma and Leydig tumor cells showed a marked decrease in nuclear expression of p44 and protein arginine methyltransferase 5 with a concomitant marked increase in cytoplasmic expression of these proteins. Furthermore, average testicular size was increased by 29% in p44(+/-) heterzygotic mice. CONCLUSIONS: These results suggest distinct functions of the nuclear and the p44/protein arginine methyltransferase 5 complexes in the developing fetal testis and in the oncogenesis of testicular tumors. Further studies are needed to confirm the functional relevance of these findings.

Florid cystic endosalpingiosis presenting as an obstructive colon mass mimicking malignancy: case report and literature review.

CASE REPORT: We report a case of transmural florid cystic endosalpingiosis of the colon with tumor-like obstruction in a 90-year-old woman with abdominal distention and obstruction. PATHOLOGICAL FINDINGS: Colonoscopy examination revealed an obstructive luminal mass. Pathologic examination of the sigmoid colectomy specimen revealed a transmural, florid proliferation of mostly cystically dilated glands that were lined by epithelium that varied from flattened to ciliated tubal-type cells typical of endosalpingiosis. The pathologic diagnosis of florid cystic endosalpingiosis of the colon was made based on characteristic microscopic features and the immunoprofile. To our knowledge, this is only the second reported case in the English literature of this entity presenting as an obstructive colon mass.

Translocation efficiency of apolipoprotein B is determined by the presence of beta-sheet domains, not pause transfer sequences.

Cotranslational translocation of apoB100 across the endoplasmic reticulum (ER) membrane is inefficient, resulting in exposure of nascent apoB on the cytosolic surface of the ER. This predisposes apoB100 to ubiquitinylation and targeting for proteasomal degradation. It has been suggested that pause transfer sequences (PTS) present throughout apoB cause inefficient translocation. On the other hand, our previous study demonstrated that the translocation efficiency of apoB100 is dependent on the presence of a beta-sheet domain between 29 and 34% of full-length apoB100 (Liang, J.-S., Wu, X., Jiang, H., Zhou, M., Yang, H., Angkeow, P., Huang, L.-S., Sturley, S. L., and Ginsberg, H. N. (1998) J. Biol. Chem. 273, 35216-35221); this region of apoB has no PTS. However, the effects of the beta-sheet domain may require the presence of PTS elsewhere in the N-terminal region of apoB100. To further investigate the roles of PTS and beta-sheet domains in the translocation of apoB100 across the ER, we transfected McArdle RH7777, HepG2, or Chinese hamster ovary cells with human albumin (ALB)/human apoB chimeric cDNA constructs: ALB/B12-17 (two PTS but no beta-sheet), ALB/B29-34 (beta-sheet but no PTS), ALB/B36-41 (two PTS and a beta-sheet), and ALB/B49-54 (neither PTS nor a beta-sheet). ALB/ALB1-40 served as a control. Compared with ALB/ALB1-40, secretion rates of ALB/B12-17, ALB/B29-34, and ALB/B36-41 were reduced. Secretion of ALB/B49-54 was similar to that of ALB/ALB1-40. However, only ALB/B29-34 and ALB/B36-41 had increased proteinase K sensitivity, ubiquitinylation, and increased physical interaction with Sec61alpha. These results indicate that the translocation efficiency of apoB100 is determined mainly by the presence of beta-sheet domains. PTS do not appear to affect translocation, but may affect secretion by other mechanisms.

Overexpression of human diacylglycerol acyltransferase 1, acyl-coa:cholesterol acyltransferase 1, or acyl-CoA:cholesterol acyltransferase 2 stimulates secretion of apolipoprotein B-containing lipoproteins in McA-RH7777 cells.

The relative importance of each core lipid in the assembly and secretion of very low density lipoproteins (VLDL) has been of interest over the past decade. The isolation of genes encoding diacylglycerol acyltransferase (DGAT) and acyl-CoA:cholesterol acyltransferases (ACAT1 and ACAT2) provided the opportunity to investigate the effects of isolated increases in triglycerides (TG) or cholesteryl esters (CE) on apolipoprotein B (apoB) lipoprotein biogenesis. Overexpression of human DGAT1 in rat hepatoma McA-RH7777 cells resulted in increased synthesis, cellular accumulation, and secretion of TG. These effects were associated with decreased intracellular degradation and increased secretion of newly synthesized apoB as VLDL. Similarly, overexpression of human ACAT1 or ACAT2 in McA-RH7777 cells resulted in increased synthesis, cellular accumulation, and secretion of CE. This led to decreased intracellular degradation and increased secretion of VLDL apoB. Overexpression of ACAT2 had a significantly greater impact upon assembly and secretion of VLDL from liver cells than did overexpression of ACAT1. The addition of oleic acid (OA) to media resulted in a further increase in VLDL secretion from cells expressing DGAT1, ACAT1, or ACAT2. VLDL secreted from DGAT1-expressing cells incubated in OA had a higher TG:CE ratio than VLDL secreted from ACAT1- and ACAT2-expressing cells treated with OA. These studies indicate that increasing DGAT1, ACAT1, or ACAT2 expression in McA-RH7777 cells stimulates the assembly and secretion of VLDL from liver cells and that the core composition of the secreted VLDL reflects the enzymatic activity that is elevated.